Ts65Dn mice are a model of Down syndrome and may be useful as a model Alzheimer's disease as well. Alzheimer's patients lose basal forebrain cholinergic (BFC) neurons and cholinergic function. Similarly, Ts65Dn mice lose BFC neuronal markers earlier than control littermates, but the functional effects of this loss has not been examined. This proposal will examine the functional effects of premature loss of BFC neurons in Ts65Dn mice on learning tasks that depend on the BFC system and two areas it innervates, the hippocampus and prefrontal cortex. To this end, learning will be assessed in tasks that have been shown to be dependent on BFC function (delayed non-match and match to sample, radial arm maze spatial working memory, and passive avoidance), the hippocampus (spatial, but not non-spatial, radial arm maze) and/or prefrontal cortex (behavioral flexibility). Further, we will relate learning in these tasks to BFC neuronal number and function at 3 ages that span the progression of BFC loss in Ts65Dn mice. Importantly, this proposal will determine if the cholinergic cell loss parallels the learning deficits. Data from this study may aid in understanding of the role that the loss of cholinergic neurons and function may play in dementia seen in Alzheimer's disease.